PROJECT SUMMARY/ABSTRACT The specificity of current chemo- and radiation therapy protocols used to treat clinical glioblastomas while sparing normal cells and tissues has remained a caveat for therapeutic treatments of this disease. This issue is compounded by the subtypes of glioblastoma with varying genetic profiles, making it necessary to identify novel uncharacterized therapeutic targets in these cancers. The utility of a targeted therapy approach therefore offers greater clinical benefit over standard clinical treatment modalities because of its selectivity and specificity. A targeted therapy approach is particularly advantageous for the treatment of malignant brain tumors as a means to circumvent the cellular and molecular heterogeneity of these tumors which contribute to their high rates of recurrence and therapeutic resistance. Like most human cancers the invasive nature and continued propagation of glioblastoma are governed by cytoskeletal proteins. The objective of this study is to assess Microtubule Actin Cross-Linking Factor (MACF1), a cytoskeletal integrator protein, for its role in glioblastoma. Evaluation of MACF1 as a therapeutic target in malignant brain tumors is based on preliminary data from the proposed work that supports the hypothesis that MACF1 contributes to the maintenance and progression of malignant brain tumors and will be addressed with two specific aims: 1) To ascertain MACF1 as an inhibitory target and its tumorigenic role in glioblastoma and 2) To evaluate inhibitory targeting of MACF1 as a chemosensitizer in glioblastoma. Genetic inhibitory and overexpression experiments will be used to assess anti-tumorigenic targeting and tumorigenic properties of MACF1 in glioblastoma, while biomarker expression analysis of MACF1 will be performed on various gliomas from patients. Further the effects of silencing MACF1 function will be evaluated as a sensitizer of the chemotherapeutic agent, temozolomide. The proposed research is both innovative and significant because antagonizing MACF1 function provides a single target that will impair properties of two distinct populations of proliferating and migratory invasive cells that contribute to the perpetuation and recurrence of glioblastoma; as well as identify an uncharacterized target that expands our approach to combating not only glioblastoma but other cancers that will be diagnosed in 1 out 2 persons during their lifetime.